S-monoalkylaminopropyl-sh-



United States Patent 3,126,373 S-MONOALKYLAMINOPROPYL-SH- DlBENZ-[h,t]-AZEP1NES Paul N. Craig, Roslyn, Pa., assignor to Smith Kline &

French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania No Drawing. Filed Feb. 2, 1962, Ser. No. 170,806 1 Claim. (Cl. 260-439) This invention relates to 5-monoalkylaminopropyl-SH- dibenz- [b,f] -azepines which have useful therapeutic activity, specifically as general central nervous system depressants and particularly as antiemetics, tranquilizers, calmatives, anti-histaminics, spasmolytics, antishock agents and potentiators of analgetics or anesthetics.

The novel 5-monoalkylaminopropyl-5Hdibenz-[b,f]- azepines of this invention are represented by the general formula:

R represents lower alkyl of from 1 to 4 carbon atoms,

preferably methyl.

This invention also includes salts of the above defined bases formed with nontoxic organic and inorganic acids. Such salts are easily prepared by methods known to the art. The base is reacted with either the calculated amount of organic or inorganic acid in aqueous miscible solvent, such as acetone or ethanol, with isolation of the salt by concentration and cooling or an excess of the acid in aqueous immiscible solvent, such as ethyl ether or chloroform, with the desired salt separating directly. Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylene-salicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicyclic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, pa1mitic,'itaconic, glycolic, p-aminobenzoic, glntamic, benzene sulfonic and theophylline acetic acids as well as with the S-halotheo phyllines, for example, 8-bromotheophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. Of course, these salts may also be prepared by the classical method of double decomposition of appropriate salts which is well-known to the art.

The compounds of this invention are characterized by singular central nervous system activity in comparison to the 5-dialkylaminopropyl-SH-dibenz-[b,f]-azepines. The unique central nervous system activity of the S-monoalkylamino derivatives of this invention is characterized particularly by a calmative activity and may be best demonstrated by pharmacological testing of protective eifects on stress induced ulcers in rats. In this test procedure, rats are subjected to a severe psychological stress, namely complete restraint including limb immobilization. This situation induces ulcers of the gastric mucosa after several hours. This response (ulcers) is used as a measure of a specific type of psychlogical stress. Test compounds are evaluated in this procedure for their protective effect against such stress induced ulcers. Results in this test obtained for 5-(3'-methylaminopropyl)-5H-dibenz-[b,f]- azepine (SK & F #13943), a typical compound of this 3,126,373 Patented Mar. 24, 1964 2 invention, and 5-(3-dimethylaminopropyl)-5H-dibenz- [b,f]-azepine (SK & F #5355) are given in Table 1. The effective dose value for 50% of the test animals (ED is determined by subcutaneous (s.c.) administration of the test compound at graduated doses to groups of 15 rats per dose.

TABLE 1 calmativeActivity Anti-Furmethide Protective Effect Activity Against Stress (Isolated Rabbit Induced Ulcers Jeiunum) Structure and No.

Mini- EDau Relative mum Relative rug/kg. Potency Dose, Potency.

s.c. mg./50

SK & F #5355 O 2.0 1 0.01 1 H2)sN\ SK & F #13943 I: i 0.13 15.4 0.04 .25 i 2)s The dimethylamino compound, SK & F #5355, produces protection in this stress induced situation, having an effective does for 50% of the test animals (ED of 2.0 mg./kg. However, the monomethylamino compound, SK & F #13943, is much more effective, with an ED of 0.13 mg./kg., which is 15.4 times as potent as SK & F #5355. Both compounds were further compared for their local anti-chlolinergic effect by testing them according to standard procedures for antagonism of furmethide induced spasm of intestinal strips. The minimum antie furmethide doses are given above in Table 1. SK & F #13943 is only A as potent as SK & F #5355 in this atropine-like activity.

Therefore, the compound representative of this invention, SK & F #13943, has greater protective activity (15.4

' times) than the dimethylamino compound, SK & F #5355,

in the stress induced ulcer procedure, even though its local anti-cholinergic activity is only A as potent as SK & F #5355. It is concluded therefore, that SK & F #13943 has a greater central nervous system protective activity than SK & F #5355. Quantitatively, SK & F #13943 has 60 times (15.4/0.25) the central nervous system'p rotective activity of SK & F #5355.

Particularly significant in-these test results is the fact that not only is the degree of potency of the compounds of this invention increased dramatically but the kind of activity demonstrated is distinct from corresponding 5-di alkylamino derivatives. For example, as a calmative the 5-monomethylaminopropyl compound, SK & F #13943, is considerably more potent than the S-dimethylaminopropyl compound, SK & F #5355, (15.4 times as seen in protection of stress induced ulcers). However, since SK & F #13943 is only A as potent as SK & F #5355 in the local anti-cholinergic test procedure, it must be concluded that the calmative activity of the compounds of this invention is exerted on the level of the central nervous system rather than on the peripheral level. Therefore it is this selective 3,1 3 quantitative increase in potency, achieved by a central nervous system activity, which distinguishes the compounds of this invention from the -dialkylaminopropyl- 5H-dibenz-[b,f]-azepines.

Table 2 presents the data compared to the effects of atropine.

tuted in the 5-position are prepared from the corresponding iminodibenzyls by dehydrogenation in accordance with the method disclosed in copending application Serial No. 688,442, filed October 7, 1957, now Patent No. 3,074,931. As disclosed therein, the iminodibenzyl is heated in the presence of a dehydrogenation catalyst either in the vapor TABLE 2 Anti-Furmethide Anti-Ulcer Activity Effect (isolated rabbit jejunum) Central Activity Structure and No. Index Miniy/x ED Atropine mum Atropine (mg./kg.) Ratio Dose Ratio (y) -I cc.)

Atropine CHg-CHCH1 CHgOH N-CH; CHOCOCH 0.30 1 .0007 1 1 CHz-(1H- H2 SK & F #5355 I? CE; 2.0 01 08 1. 9 (CH1) N\ SK 6: F #13943 0. 13 2. 31 04 02 115. 5 N /H (HDS The monomethylamino compound, SK & F #13943 is 2.3 times as potent as atropine in the protection of stress induced ulcers, while the dimethylamino compound, SK & F #5355, is about 0.1 as potent as atropine. In the test for antagonism of furmethide induced spasm, both compounds were less active than atropine. Again of particular significance is the fact that SK & F #13943 has greater protective activity than atropine against stress induced ulcers even though its local anti-cholinergic activity is only 0.02. that of atropine. Therefore on the basis of central nervous system protective activity, the monomethylamino compound, SK & F #13943, is 115 times more potent than atropine, whereas the dimethylamino compound, SK & F #5355, has only 1.9 times the activity of atropine. These results further demonstrate the striking selective potency of the compounds of this invention.

The starting materials for preparing the S-monoalkylaminopropyl-dibenzazepines have the following structural formula:

FORMULA 2 when: R and R represent hydrogen or chlorine.

The dibenzazepines of Formula 2 which are unsubstiphase, alone or in a solvent. Preferably the dehydrogenation is carried out by vaporization of the iminodibenzyl under reduced pressure in the presence of palladium on charcoal. The reaction product is purified by crystallization or chromatography.

The preparation of the 5-unsubstituted iminodibenzyls used as intermediates as outlined above is likewise disclosed in the aforesaid application Serial No. 688,442, now Patent No. 3,074,931.

The 5-unsubstituted dibenzazepines of Formula 2 are converted to the therapeutically valuable 5-monoalkylaminopropyl-5H-dibenz-[b,f]-azepines of Formula 1 as follows. The sodio derivative of the S-unsubstituted dibenzazepine is reacted with 'y-bromopropyl tetrahydropyranyl ether in xylene, the pyranyl group is removed by careful hydrolysis with hydrochloric acid and the 7- hydroxy compound is acylated with excess p-toluenesulfonyl chloride in pyridine. The 5-(3-hydroxypropyl)- 5H-dibenz-[b,f]-azepine p-toluenesulfonate thus prepared is reacted with an excess of a lower alkyl amine in an alkanolic solvent for approximately 10 hours at reflux or in a sealed tube to give the product after suitable workup.

The 5-monoalkylaminopropyl-SH-dibenz-[b,f]-azepines of this invention may be advantageously prepared from substituted dibenzyls in an alternative manner, namely, by alkylating a 2-amino-2-halodibenzyl under conditions identical with those described above for the 5alkylation of the dibenzazepines and subsequently cyclizing the dibenzyl to form the alkylated iminodibenzyl which is in turn dehydrogenated under conditions described hereabove to give the desired compounds.

The above cyclization of a 2-monoalkylaminopropylamin-2'-halodibenzyl is carried out by heating the compound in the presence of an acid-binding agent, present in at least an amount sufiicient to neutralize the hydrohalic acid formed during the reaction. Exemplary of such acid-binding agents are the carbonates, such as sodium carbonate, sodium bicarbonate or preferably potassium carbonate. The reaction is run in a suitable, nonreactive organic solvent in which the reactants are at least partially soluble. Exemplary are dioxane, dimethylaniline, diethylformamide, methylformamide, dimethylformamide or dimetihylacetamide. Preferably, the solvent is dimethylformamide and other similar lowercarbon amides.

Optimum yields in this cyclization are obtained when catalytic amounts of copper or copper bronze powder are added, for instance up to 5% by weight of the dibenzyl. The reaction mixture is advantageously heated at from about 100 to 220 C. for long periods, such as from 4 to 60 hours. Preferably, the reaction mixture is heated with stirring at the boiling point of the solvent for from about 8 to 24 hours. The reaction mixture is Worked up by cooling, filtering and quenching in water. The separated product is washed and purified to give the desired iminodibenzyl.

Alternatively, a 5-unsubstituted iminodibenzyl may be alkylated as described above and the thus alkylated iminodibenzyl may be converted to the corresponding alkylated dibenzazepine by means of a dehydrogenation catalyst in accordance with the process disclosed in copending application Serial No. 688,442, new Patent No. 3,074,931.

Further the 5-monoalkylaminopropyl-5H-dibenz-[b,f]- azepines may be prepared by reacting the 5-unsubstituted dibenzazepine with an excess of acrylonitrile or in an inert solvent such as benzene in the presence of a catalytic amount of a strong base, such as a quaternary base, for instance benzyltrimethylammonium hydroxide. The resulting fl-cyanoethyl compound is then reduced, for instance with lithium aluminum hydride to give the primary amine. Further alkylation of the primary amine by for example with a reactive ester such as an alkyl halide in the presence of an acid-binding agent as described above in an inert solvent such as benzene or xylene gives compounds of this invention.

Of particular advantage as preparative procedures for obtaining the 5-monoalkylaminopropyl-SH-dibenz-[b,f]- azepines are the N-alkylation of dibenzazepines in the 5- position of the nucleus, and the dehydrogenation of 5- alkylated iminodibenzyls by a suitable catalyst such as palladium on charcoal.

The following examples are not limiting but are illustrative of compounds of this invention and the procedures for their preparation and Will serve to make fully apparent all of the compounds embraced by the general formula given above and the preparation thereof respectively.

Example 1 An electrically heated glass column, 35 mm. in diameter and 30 cm. long, is packed with 1.0 g. of 30% palladium on charcoal sprinkled on glass wool and 4.5 g. of 10,11-dihydro-[b,f]-azepine is sublimed through the column at 0.5 mm. by heating until sublimation occurs. The upper part of the column is surrounded by a Dry Ice bath and after two hours the reaction is completed. The yellow sublimate is removed and purified by chromatography through alumina, using benzene, to give the product, 5H-dibenz-[b,f]-azepine, M.P. 196.5l98 C.

A solution of 4.05 g. of 5-(3'-hydroxypropyl)-5H-dibenz-[b,f] -azepine p-toluenesulfonate (prepared from the reaction of the sodio derivative of 5H-dibenz-[b,f]-azepine, with 'y-bromopropyl tetrahydropyranyl ether in xylene, removing the pyranyl group by careful hydrolysis with hydrochloric acid and acylating the 'y-hydroxy compound with excess p-toluenesulfonyl chloride in pyridine) and 1.0 g. of methylamine in 25 ml. of ethanol is heated for 10 hours in a sealed tube. The solvent is removed from the reaction mixture and the residue is extracted with a water-chloroform mixture. The chloroform layer is extracted with dilute mineral acid and the extracts are neutralized with sodium carbonate solution. The crude product is extracted into ethyl acetate and removal of the solvent yields 5-(3'-methylaminopropyl)-5H-dibenz- [b,f]- azepine.

Treating the free base in ether solution with ethereal hydrogen chloride gives the corresponding hydrochloride salt.

Following the above procedure and using an excess of ethylamine in a sealed tube, 5-(3-ethylaminopropyl)-5H- dibenz-[b,f]-azepine is obtained.

Example 2 Following the general procedure outlined in Example 1, 2.5 g. of 3,7-dichloroiminodibenzyl (Belgian Patent #541,489) is sublimed through a glass column packed with 0.5 g. of 30% palladium on charcoal sprinkled on glass wool. After two hours, the collected material from the cooled part of the column is removed and purified to give 3,7-dichloro-5H-dibenz-[b,f]-azepine as yellow crystals.

A solution of 4.7 g. of 3,7-dichloro-5-(3'-hydroxypropyl)-5H-dibenz-[b,f] -azepine p-toluenesulfonate (prepared from the reaction of the sodio derivative of 3,7- dichloro-SH-dibenz- [b,f] -azepine with 'y-bromopropyl tetrahydropyranyl ether in xylene, removing the pyranyl group by careful hydrolysis with hydrochloric acid and acylating the v-hydroxy compound with excess p-toluenesulfonyl chloride in pyridine) and 1.5 g. of butylamine in 30 ml. of ethanol is heated at reflux for ten hours. The solvent is removed from the reaction mixture and the residue is extracted with a water-chloroform mixture. The chloroform layer is extracted with dilute mineral acid and the extracts are neutralized with sodium carbonate solution. The crude product is extracted into ethyl acetate and the solution is heated with maleic acid to yield 3,7-dichloro-5-(3-butylaminopropyl) 5H dibenz- [b,f]-azepine maleate.

Following the above procedure and using an excess of methylamine or ethylamine in a sealed tube, 3,7-dichloro- 5-(3'-methylaminopropyl) 5H-dibenz-[b,f]-azepine and 3,7-dichloro-5-(3-ethylaminopropyl) 5H dibenz-[b,f]- azepine are obtained, respectively.

This application is a continuation-in-part of copending application Serial No. 688,442, filed October 7, 1957, now Patent No. 3,074,931.

What is claimed is:

A chemical compound selected from the group consisting of a free base and the nontoxic acid addition salts thereof, the free base having the formula:

10 11 C H O H 8 R3- i 5 -3.1 6 4 H C H1O Hg 0 H N References Cited in the file of this patent UNITED STATES PATENTS Cusic Feb. 24, 1953 Jacob et al Mar. 12, 1957 

